Currently, as a method for administrating a medicament, it is often used to spray a liquid drug preparation put in a spray container, to a mucosa and skin of a lumen and body surface. Especially, a drug preparation for intranasal administration is often used. The medicaments used for this purpose had been limited to a regional use such as a treatment for rhinitis. However, these days such administration is getting some attention for the purpose of systemic action. Low-molecular medicaments for systemic action such as butorphanol and sumatriptan, and peptidic medicaments such as calcitonin and desmopressin have been already sold in the market as a drug preparation for intranasal administration, and furthermore a lot of new applications via intranasal administration have been tried to get some absorption-improvement or fast-act.
The merits of a drug preparation for spray-administration to mucosa, especially a drug preparation for intranasal administration include that (1) fast act of a drug is expected because of its rapid absorption, (2) it is possible to avoid the decomposition of a drug due to the first-pass in liver, (3) it is possible to avoid the decomposition of a drug due to gastric acid or gastrointestinal enzyme in gastrointestinal tract, (4) it is possible to reduce the dose of a drug because of its high bioavailability, (5) it is a noninvasive administration compared with injection, (6) a patient can treat himself/herself, (7) a drug can directly reach the blood circulation or central nervous system, etc., while the demerits of a drug preparation for intranasal administration include that (1) the dose of a drug which can be administered to nasal cavity is limited to 25-200 μL per one operation, (2) a compound having a high molecular weight of 1 kD or more is hard to be absorbed via this route, (3) the absorption of a drug might be affected by the pathological state of nasal cavity, (4) the state of nasal cavity is varied between individuals, (5) the elimination system by mucociliary clearance might affect the absorption of a drug, (6) intranasal enzyme barrier exists, (7) nasal mucosa might be irritated by a drug, etc.
Nasal cavity is a site which first gets in contact with the outside, as well as oral cavity, which have a very outstanding character about the foreign-material-removal and prophylaxis. The abnormal activation of these actions or the failure thereby can cause rhinitis, nasal allergy, etc. Especially, pollinosis (hay fever) is becoming a serious social problem. For the purpose of the treatment of these nose-localized diseases, a lot of nasal spray preparations containing a vasoconstrictor agent, an antiallergic drug, a steroid, etc. have been put on the market.
Recently, some nasal absorption-type preparations containing a bioactive peptide or a water-soluble peptide having a molecular weight of 1000-3000 have been put on the market. These water-soluble high-molecular medicaments are ineffectual via oral administration, but effective only via injection. However, nasal administration can arrive at high bioavailability of several % to several 10%. The main reason thereof is thought that the permeability of epithelial layer in nasal mucosa which is an absorption path for water-soluble high-molecular medicaments is even higher than that of gastrointestinal tract or other mucosa. Thus, a nasal absorption-type preparation containing a water-soluble high-molecular medicament which is expected as a systemically effective formulation, is thought to be very useful as a noninvasive formulation type instead of an injection formulation.
Recently, a nasal absorption-type preparation which can be expected to mitigate an acute pain has been researched/developed as a narcotic analgesic and a migraine drug, on the basis of the fact that the permeability of epithelial layer in nasal mucosa is superior to that of other mucosa. A nasal absorption-type preparation containing such a medicament having central nervous system effect can markedly contribute the improvement of a patient's QOL, because it is expected to exert the pharmacological action more rapidly than a preparation for oral administration and it is possible to be administered by patient itself. A nasal cavity has a NALT (nasal-associated lymphoid tissue) which is similar to a lymphoid tissue. These days, some drug preparations for intranasal administration comprising influenza vaccine, diphtheria vaccine, etc. have been researched/developed as a vaccine-administration route for airborne-infectible virus, because the nasal immunoresponsiveness is high. Thus, it is so expected that a drug preparation for intranasal administration would be developed on the basis of the anatomical/physiological property of nasal cavity. However, for the drug design thereof it is required to understand the anatomical/physiological property of nasal cavity and surrounding tissue thereof.
A drug preparation for intranasal administration needs creative strategies because the clearance from nasal cavity is high. The preparation types for nasal cavity which have been developed include an ointment preparation, a droplet preparation, a spray-type preparation, a powder preparation, etc. These preparations are designed/developed so that an active medicament should effectively exert its effect in nasal cavity or be absorbed via the nasal cavity, i.e., the intranasal dispersibility of the preparations should be enhanced or the intranasal retention (adhesive property) should be enhanced, in order that the contacting time between an active medicament and nasal mucosa may be lengthened (JP-B-2011069).
An ointment preparation for nasal cavity is not so sanitary because it is usually put on with a finger, and additionally it is difficult to administer a predetermined amount of an active medicament because it is impossible to let the medicament reach the mucosa of deep nasal cavity with a finger.
A droplet preparation has been the most simple preparation for nasal cavity, however, it is difficult to accurately apply a predetermined amount thereof and further the applied medicament is removed from nasal cavity to pharynx through the mucociliary clearance.
A spray-type preparation is more dispersible than a droplet preparation because a liquid preparation can be pumped up, nebulized and intranasally sprayed.
A powder preparation is useful at the time of using a medicament decomposable in a solution or when the retention in nasal cavity should be held. However, the intranasal administration of a powder preparation might sometimes bring about some uncomfortable feelings and disorder of mucosa, and it is difficult to design a preparation having uniform particles.
Amongst these drug preparations for intranasal administration, a spray-type preparation is the most common preparation type because of its simplicity and comfortable feeling. On a spray-type preparation, some trials to enhance the efficacy and the absorption of a medicament have carried out by widening the contacting area between a medicament and nasal mucosa, and -lengthening the contacting time thereof, i.e., improving the retention of a medicament.
On conventional spray-type preparations, it is recommendable to suck air from nose at the time of the spray operation, in order to prevent holding a medicament at nasal vestibule or prevent the sprayed preparation from dripping off from nasal cavity. However, it is thought that the elastic tissue of nasal valve narrows by sucking air, and then almost all of the preparation is carried from nose to mouth and finally swallowed.
The liquid-spraying device which has been usually used in the past is made for a spray-type preparation for liquid formulation wherein a liquid formulation is pumped up through a tube, which is generally used at an angle between about 0-25° (see FIG. 3). For this device, it is necessary to put the tip of the tube in the liquid, and thus the spray angle of the spray container for administration needs to be set at around 0° and a patient needs to tilt his/her head forward, which is a reason for setting at an angle between about 0-25°. However, using this administration system, a normal liquid formulation which has no viscosity or no adhesion, or is low viscosity will instantly run to nostril. On the contrary, using this administration system as a patient tilts his/her head back and the spray angle of the spray container for administration is set at about 65-90°, a normal spray-type liquid preparation sprayed will be hit on the intranasal wall such as turbinate and nasal septum, and then drained to inferior meatus of nose because of its non-adhesion, and mostly ended up being carried to his/her mouth and swallowed. It is partially possible to prevent the liquid from running to inferior meatus of nose by adding an adhesive polymer mentioned later as a substrate of the formulation. However, when an adhesive polymer is used therein, it is thought that the particle size of the formulation sprayed gets bigger; the liquid cannot be widely dispersed since the spray spreading-angle from the spray container gets smaller; the particles collide with each other in a nose to get bigger particles which is hit on the wall; and many of the formulation end up being carried to a mouth and swallowed. Further, it is expected that the liquid can be spread at a wide area of the turbinate by spraying it with wider spray angle, however, thereby it becomes impossible to put the tip of the tube for pumping up in the liquid in case of a conventional spray-type preparation. Therefore, there was some limitations to administer a liquid formulation as a patient tilts his/her head back and the spray angle of the spray container for administration is set at a desired angle.
In addition, the above-mentioned spray device for liquid is a system absorbing external air and thus it is necessary to use a certain amount of an antiseptic agent or other agent.
In addition, the particle size sprayed from the spray device to nasal cavity is also one of the factors to be considered in order to improve the clearance of a medicament. That is to say, the nasal cavity of a human has an area of about 150-180 cm2, the distance from nostril to nasopharynx is 12-14 cm as a straight line which is very long, a nasal cavity has an optimized, narrow, and complicated geometric structure in order to protect the lower respiratory tract, and the narrow slit of the nasal valve causes about a half of the total air-resistance in nasal cavity. Further, there are some spaces partitioned in a slit like partition with turbinate in the backside of the nasal valve, where the speed of the formulation particles sprayed slows down and the particles can be contacted with nasal mucosa and dispersed. However, in such complicated and winding intranasal cavity, the formulation particles sprayed should been easily hit on the intranasal wall to be caught and deposited. Therefore, most of the formulation particles sprayed to nasal cavity whose particle size is 5 μm or more should be caught by the nasal cavity, then the formulation particles hit on the intranasal turbinate mucosa to be caught and deposited should be carried backward by means of the ciliary movement of ciliated cells covering the mucosa, and finally, via posterior nasal cavity and pharynx, drained to the month or swallowed. The countermeasure for the clearance of an active medicament which is taken as a foreign material by cilia and mucus (mucociliary clearance) is the most important factor on the design of a drug preparation for intranasal administration. The efficacy and the absorption of a medicament in nasal mucosa can be decided mainly based on the retention of a medicament (adhesive property of a formulation) and the permeability of a medicament at the capture part of nasal mucosa. A medicament administered to the effective capture part of nasal mucosa should disappear from the capture part as a simultaneous reaction mainly by means of the removal toward esophagus and respiratory tract due to the mucociliary clearance and the absorption to nasal mucosa cell via nasal mucosa. When the removal toward esophagus and respiratory tract from the effective capture part is quick, the clearance for the absorption to nasal mucosa cell should be reduced and the bioavailability thereof should be reduced. Or, the intranasal area which the formulation reaches can be improved to expand when the particle size of the sprayed formulation is micrified, however, thereby the risk that the formulation could reach lungs increases. Therefore, it has been understood for a skilled person to consider the balance of the particle size. Accordingly, in order to increase the clearance for the absorption to nasal mucosa and improve the absorption, it is important to optimize the particle size of the sprayed formulation, to spray in a suitable spray spreading-angle and an uniform spray spread, and further to add the retention of a medicament, i.e., adhesive property of a formulation for nasal mucosa, and thus it has been necessary to add an adhesive polymer as a base material for formulation to improve the property.
In theory, it is possible to spray a formulation for nose to take the formulation to the backside of the nasal valve by controlling the particle size of the sprayed formulation in a size of not more than 50 μm using a nebulizer, and inbreathing the sprayed particles at the time of spraying. However, using particles in a size of not more than 50 μm, a half or more of the particles should reach bronchi or lung, and thus a medicament to be held in intra cavity should disappear and additionally an undesirable side effect might happen. Further, the device for spray operation such as a nebulizer is expensive, and there was not any inexpensive and simple system to spread a formulation having an effective particle size in a whole intranasal cavity.
In order to improve the retention of a spray-type preparation in intranasal cavity, the present inventors have invented a gel base material for spray-administration to mucosa or skin, and have already disclosed a sprayable gel base material and a sprayable gel preparation comprising said base material and an active medicament, which can be applied to nasal cavity that is a mucosa site and is possible to use as a high-spreading spray-type preparation for nose (JP-B-2011069).
However, it has been already known as a serious problem that the viscosity should be reduced through spray operation even when a high viscous sprayable gel preparation is sprayed.
In addition, it is sometimes difficult to keep a constant amount of one spray shot when the spray angle for administration is rapidly changed, etc. because the sprayable gel-type preparation adheres on the sidewall of the spray container in being used as a spray-type preparation due to its high viscosity, the residual rate that indicates an unsprayed formulation retained in the container is high compared with a conventional liquid formulation, and the preparation cannot flow easily and rapidly in the spray container. Furthermore, it is also a problem that the formulation particles sprayed hardly reach the deep nasal cavity due to their particle size distribution, and it is difficult to adjust the spray spreading-angle and to spray in a uniform spray spread.
On a preparation for spray-administration to skin, there are also some similar problems to the above-mentioned preparation using a nasal spray such as the retention of the preparation, and the spray angle of the spray container for administration.